Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy.

BACKGROUND: Complement 3 glomerulopathy (C3G) results from dysfunction of the alternative complement pathway (ACP). No data are available on post-transplant C3G in South Asia. METHODS: In this study, renal allograft biopsies of C3G patients performed from 2012 to 2017 were analysed for ACP functional assay (APFA), serum complement levels, complement factor H (CFH), complement factor B (CFB) and autoantibodies to CFH and CFB. Limited genetic screening for CFH/CFHR5 genes was carried out. All study patients were also followed up. RESULTS: A total of 21 cases of C3G were included, of which 11 had native C3G disease (that is, recurrent C3G). Of these 11 recurrent cases, 7 presented with allograft dysfunction and 4 with proteinuria and renal dysfunction. Early post-transplant recurrence (<1 month) was noted in six patients, whereas recurrence in five patients occurred within 8-17 months of transplant. Biopsies showed mild focal mesangial expansion with or without endocapillary proliferation and thrombotic microangiopathy. Rejection was also noted in six patients. APFA/C3 levels were low in all cases. Serum CFH levels were low [dense deposit disease (DDD), 44%; C3 glomerulonephritis (C3GN), 25%], whereas CFB levels were normal. Autoantibodies to CFH, CFB and C3 nephritic factor were present in 11, 0 and 44% of DDD cases, respectively, and in 17, 17 and 33% of C3GN cases, respectively. Genetic analysis revealed only non-pathogenic CFH gene variants (93%). No novel mutation was found. At follow-up (140 months), stable graft was noted in 28% of cases, progressive renal failure in 19%, graft loss in 34%, and 19% of patients died. CONCLUSION: Post-transplant C3G can present with graft dysfunction and/or proteinuria. Subtle histological findings demand careful interpretation of immunofluorescence results. Autoantibodies to complement pathway regulatory proteins are common, and no novel mutation has been found from limited genetic workup. Clinical outcome is poor.

Fungal infection in post-renal transplant patient: Single-center experience.

INTRODUCTION: Fungi are ubiquitous organisms and significantly alter the post-transplant course. They are a major cause of morbidity and mortality and more so in developing countries. AIMS: To study the clinical profile, etiology, risk factors, treatment, and outcome of fungal infections in post-renal transplant recipients. MATERIALS AND METHODS: This was a cross-sectional observational retrospective study from January 2014 to June 2017 wherein renal transplant recipients with invasive fungal infection were included and were followed. RESULTS: Amongst 550 renal transplant recipients, 56 (10.2%) patients developed invasive fungal infection. Mean age of patients was 40.61 ± 10.06 (13-66) years and mean duration of acquiring infection post-transplant was 25.33 ± 23.65 (1-96) months. Male to female ratio was 3:1. Fever was the commonest presentation observed in 89.3% patients. Cough (76.8%), breathlessness (64.3%), sputum (55.3%), hypoxia (50%), and hemoptysis (10.7%) were other common clinical symptoms at presentation. Mean serum creatinine at presentation was 1.70 mg/dl. Most common invasive fungal infection isolated was Mucormycosis 15 (26.7%), foolwed by Aspergillosis 13 (23.2%), Pneumocystis jiroveci 12 (21.4%), Cryptococcus 6 (10.7%), Candida 4 (7.1%), Histoplasmosis 3 (5.3%), Phaeohypomycosis 2 (3.5%), and 5 (8.9%) patients had undetermined fungal etiology. Twenty (35.7%) patients had evidence of dual infection. Use of antithymocyte globulin 27 (48.2%), post-transplant diabetes mellitus 18 (32.1%), Cytomegalovirus (CMV) infection 16 (28.5%), anti-rejection therapy 9 (16%), and Hepatitis C infection 7 (12.5%) were some identified risk factors. Ten (17.8%) patients had graft loss and 12 (21.4%) patients died in the study period. CONCLUSIONS: Invasive fungal infection is a serious threat to renal transplant recipients. Patient and graft survival is significantly affected by fungal infection in developing world.

Contribution of Clinically Indicated Repeat Renal Biopsy in Indian Patients with Lupus Nephritis.

BACKGROUND: Repeat renal biopsy is usually done for lupus nephritis (LN) flare or resistant disease. We analyzed the changes between first and repeat biopsy and the contribution of repeat biopsy on renal outcome in LN patients. METHODS: This was a retrospective study carried out at a tertiary care center in India. Sixty-two LN patients who underwent repeat biopsy for clinical indications, between January 2012 to December 2016, were included. Clinical and histological parameters at first and second biopsies were compared. Logistic regression analysis was done to determine parameters on repeat biopsy predicting response at last visit. RESULTS: Repeat biopsy was done for relapse in 56% and for resistant disease in 44% patients. Seven (13.7%) out of 51 patients with baseline proliferative histology converted to non-proliferative lesion on second biopsy, while 2 (18.2%) out of 11 with baseline non-proliferative lesion converted to proliferative lesion on second biopsy. On repeat biopsy, the presence of endocapillary proliferation decreased, whereas glomerulosclerosis, interstitial fibrosis/tubular atrophy (IFTA), and glomerular basement membrane thickening increased. At the last visit (median follow-up of 38.6 months after first biopsy and 13.8 months after second biopsy), 79% of patients were in remission and 6.5% needed renal replacement therapy. The presence of IFTA >30% and thrombotic microangiopathy (TMA) on second biopsy independently predicted response at last visit. CONCLUSION: In Indian patients with LN, chronicity markers and superimposed membranous pattern increased on repeat biopsy done for clinical indications. The presence of IFTA and TMA on second biopsy predicted response at last visit.

Gastrointestinal Involvement in Granulomatosis with Polyangiitis: Case Report and Review.

Granulomatosis with polyangiitis (GPA) commonly affects upper/lower respiratory tract and kidneys. It causes necrotizing vasculitis of small and medium-sized blood vessels. Gastrointestinal (GI) involvement is an uncommon manifestation of GPA, and presentation with predominant GI manifestation is noteworthy. We report a case of 50-year-old male with melena due to GI vasculitis along with other systemic involvement. The patient was treated with pulse methylprednisolone, cyclophosphamide, and plasmapheresis. To manage the refractory GI bleed, the patient underwent surgical resection, and the histology of the surgical specimen confirmed necrotizing vasculitis.

Postpartum Renal Cortical Necrosis Is Associated With Atypical Hemolytic Uremic Syndrome in Developing Countries.

INTRODUCTION: Pregnancy-related acute kidney injury is the most common cause of renal cortical necrosis (RCN). Atypical hemolytic uremic syndrome (aHUS) as a cause of RCN in pregnant/postpartum is underevaluated. In the current article, we describe a series of cases of pregnancy-related RCN. METHODS: All cases with acute kidney injury (AKI) in the setting of pregnancy and postpartum state were included. Diagnosis of RCN was made by contrast-enhanced computerized tomography (nonenhancing renal cortex, enhancing medulla, and no excretion of contrast medium) or on a renal biopsy. aHUS was diagnosed in the presence of microangiopathic hemolytic anemia (thrombocytopenia, elevated lactate dehydrogenase with schistocytes on peripheral smear examination, or low haptoglobin). RESULTS: A total of 21 (17.5%) patients presented with RCN during pregnancy, all in the postpartum state. Twenty patients (95.2%) showed microangiopathic hemolytic anemia consistent with HUS and 1 (4.8%) patient had biopsy-proven thrombotic microangiopathy. Low complement 3 or activation of an alternate complement pathway was seen in 9 of 15 patients in which it was done. At the end of 6 months, only 2 (9.5%) patients had partial recovery of renal functions, 5 (23.8%) patients died, and 14 remained (66.7%) on hemodialysis. CONCLUSION: The clinical and laboratory features are highly suggestive of aHUS in more than three-fourths of cases with postpartum RCN. Investigations are needed to look for genetic abnormalities in the complement pathway.

Persistent CD-19 depletion by rituximab is cost-effective in maintaining remission in calcineurin-inhibitor dependent podocytopathy.

AIM: A significant proportion of patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are either steroid dependent or steroid resistant, requiring long-term calcineurin inhibitors (CNI) use. Rituximab has more favourable safety profile. The present study was undertaken to evaluate the efficacy and safety of rituximab in CNI-dependent patients. METHODS: This was a prospective observational study conducted from July 2014 to February 2018. Steroid-dependent nephrotic syndrome or steroid-resistant nephrotic syndrome (biopsy proven MCD/FSGS), who were CNI dependent were enrolled. Mean age at enrolment was 22.77 ± 7.45 years. All patients received rituximab at a dose of 375 mg/m2 at entry in the study. CD-19 levels were monitored monthly and patients having CD-19 levels >5/µL and/or > 1% received additional low-dose (100 mg) of rituximab. RESULTS: A total of 24 patients were followed up for 12 months. At the end of 6 and 12 months, 87.5% and 79.16% of the patients achieved remission, respectively. Eight (33.33%) patients developed relapse. The mean dose of rituximab in the first year was 791 mg. The average cost of rituximab in the first year was 487.17$. Rituximab was well-tolerated, with mild infusion reactions, respiratory tract infection and oral candidiasis in 5 (20.83%), 5 (20.83%) and 1 (4.17%) patient, respectively. CONCLUSIONS: CD-19 targeted rituximab is a safe and cost-effective agent in remission maintenance in adults with CNI dependent. Over three-fourths of the patients with CNI-dependent podocytopathy maintain clinical remission with CD-19 targeted rituximab therapy.

Membranous nephropathy with light chain restricted deposits.

The literature on membranous nephropathy (MN) with monoclonal deposits on immunofluorescence (IF) and their outcome is very scarce. We report our experience of managing five patients with this clinical entity. The mean age of the patients was 33.2 ± 6.55 years. The mean proteinuria, serum albumin and serum creatinine was 5.73 ± 2.17 g/day, 2.86 ± 0.51 g/dL and 1.34 ± 1.19 mg/dL, respectively. None of the patients had a lymphoproliferative disorder. Only one patient had an elevated free light chain ratio. Four (80%) patients were M-type phospholipase A2 receptor (PLA2R) negative (tissue and serum), and one (20%) was PLA2R related. Three (60%) cases had monoclonal IgG3/k, one IgG3/λ, whereas one patient with PLA2R positivity had an IgG3/IgG4k subtype. Two (67%) patients treated with cyclical cyclophosphamide and steroids (cCYC/GC) achieved complete remission and one patient (33%) with elevated baseline creatinine had a reduction in serum creatinine with persistent proteinuria at the end of the 12th month of follow-up. One patient with PLA2R positive MN was treated with Rituximab and is in complete remission. The patient with an elevated free light chain at baseline was treated with Bortezomib/Thalidomide/Dexamethasone, had complete remission at 12 months, however, had a progressive rise in creatinine over the next 40 months of follow-up. The current series, though limited by numbers, documents the efficacy of conventional therapies in non-malignant associated MN with monoclonal deposits on IF.

Existing creatinine-based equations overestimate glomerular filtration rate in Indians.

BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) is important for diagnosis and risk stratification in chronic kidney disease and for selection of living donors. Ethnic differences have required correction factors in the originally developed creatinine-based GFR estimation equations for populations around the world. Existing equations have not been validated in the vegetarian Indian population. We examined the performance of creatinine and cystatin-based GFR estimating equations in Indians. METHODS: GFR was measured by urinary clearance of inulin. Serum creatinine was measured using IDMS-traceable Jaffe's and enzymatic assays, and cystatin C by colloidal gold immunoassay. Dietary protein intake was calculated by measuring urinary nitrogen appearance. Bias, precision and accuracy were calculated for the eGFR equations. RESULTS: A total of 130 participants (63 healthy kidney donors and 67 with CKD) were studied. About 50% were vegetarians, and the remainder ate meat 3.8 times every month. The average creatinine excretion were 14.7 mg/kg/day (95% CI: 13.5 to 15.9 mg/kg/day) and 12.4 mg/kg/day (95% CI: 11.2 to 13.6 mg/kg/day) in males and females, respectively. The average daily protein intake was 46.1 g/day (95% CI: 43.2 to 48.8 g/day). The mean mGFR in the study population was 51.66 ± 31.68 ml/min/1.73m2. All creatinine-based eGFR equations overestimated GFR (p < 0.01 for each creatinine based eGFR equation). However, eGFR by CKD-EPICys was not significantly different from mGFR (p = 0.38). The CKD-EPICys exhibited lowest bias [mean bias: -3.53 ± 14.70 ml/min/1.73m2 (95% CI: -0.608 to -0.98)] and highest accuracy (P30: 74.6%). The GFR in the healthy population was 79.44 ± 20.19 (range: 41.90-134.50) ml/min/1.73m2. CONCLUSION: Existing creatinine-based GFR estimating equations overestimate GFR in Indians. An appropriately powered study is needed to develop either a correction factor or a new equation for accurate assessment of kidney function in the Indian population.

Successful treatment of chronic hepatitis C infection with directly acting antivirals in renal transplant recipients.

AIMS: The data regarding the treatment of chronic hepatitis C (CHC) in renal transplant recipients is lacking from the Asia-Pacific region. The aim of the present study was to assess the safety and efficacy of directly acting antivirals (DAAs) in the treatment of CHC infection in renal transplant recipients. METHODS: A total of 47 CHC infected renal transplant recipients were enrolled in this real life observational cohort analysis between March 2015 and September 2016. Presence of hepatic fibrosis/cirrhosis was assessed on transient elastography (Fibroscan). Fourteen patients were treated with Sofosbuvir and Ribavirin for 24 weeks. Twenty-two patients received Sofosbuvir and Ledipasvir and 12 patients received Sofosbuvir and Daclatasvir with (n = 3) or without (n = 31) Ribavirin for 12 or 24 weeks depending on genotype and underlying cirrhosis. Data were analyzed for safety and treatment efficacy [sustained virological response at 12 weeks (SVR12)]. RESULTS: The median baseline HCV RNA concentration in the whole group was 7.38 × 106 IU/mL (1.23 × 104 -6.36 × 107 ). The SVR12 rates were 100% in all groups except in the Sofosbuvir and Ribavirin group (86%). Transient Elastography revealed minimal or no fibrosis (F0-F1) in 31 (65.96%) patients, moderate fibrosis (F2) in 11 (23.4%) patients and cirrhosis in five (10.64%) patients. The only serious adverse effect was anaemia observed in eight (57%) patients in the Sofosbuvir and Ribavirin group. CONCLUSION: DAAs including Sofosbuvir, Daclatasvir and Ledipasvir with or without ribavirin are safe and effective for the treatment of chronic hepatitis C in renal transplant recipients.

Assessment of Liver Fibrosis by Transient Elastography Should Be Done After Hemodialysis in End Stage Renal Disease Patients with Liver Disease.

BACKGROUND AND AIMS: The patients with end stage renal disease (ESRD) are at greater risk of acquiring chronic hepatitis B or C and subsequently development of liver disease. The aim of the study was to assess liver fibrosis by transient elastography (TE) and look for factors associated with change in liver stiffness measurement (LSM) with one session of hemodialysis (HD). METHODS: Consecutive ESRD patients on maintenance hemodialysis (MHD) with suspected liver disease were enrolled. They underwent LSM by TE before and after one session of HD. Bioelectric impedance analysis was done to evaluate the volume status at the time of TE. RESULTS: Sixty-eight patients with mean age of 40 ± 14 years were included. There was a significant reduction in LSM after HD (18.5 [95% CI 14.8-23.1] vs. 11.2 [95% CI 8.8-13.7] kPa, p < 0.001), with a mean LSM reduction of 7.2 [95% CI 5.25-9.19] kPa. On stratification in two groups by net ultrafiltration during HD (> or < 2.5 liters [L]), change in LSM was substantially higher in patients when total fluid removed was > 2.5 L (8.6 [95% CI 5.7-11.5] vs. 5.1 [95% CI 2.9-7.5], p = 0.05). In 18 patients who underwent liver biopsy, LSM after HD performed better at detecting significant fibrosis, with area under receiver operating characteristics curve 0.71 [95% CI 0.46-0.97], versus 0.64 [95% CI 0.38-0.90], respectively. An LSM value of 12.2 kPa after HD was 71% sensitive and 74% specific for detection of significant fibrosis (≥ F2), while values less than 9 kPa ruled out significant fibrosis with a sensitivity and specificity of 37 and 100%, respectively. CONCLUSION: LSM by TE decreases significantly after HD in patients with ESRD on long-term MHD. Hence, TE should be done after HD for accurate assessment of liver fibrosis.

Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.

No previous study has compared mycophenolate mofetil (MMF) with low-dose cyclophosphamide (CYC) in the treatment of lupus nephritis (LN). To do so, we recruited patients with LN (class III, IV, or V) and randomized them to receive either low-dose CYC or oral MMF. Those with crescentic LN, a serum creatinine over 265 µmol/l, and neurological or pulmonary lupus were excluded. MMF was prescribed at daily doses of 1.5-3 g for 24 weeks, while CYC was administered as six fortnightly infusions of 500 mg each. All patients received three methylprednisolone injections, followed by oral corticosteroids. Maintenance therapy with azathioprine and low-dose corticosteroid was started at end of induction therapy. The primary end point was treatment response at 24 weeks, while secondary end points were complete remission, Systemic Lupus Erythematosus Disease Activity Index and adverse events. Of the 173 patients recruited, 100 were equally randomized to receive either CYC or MMF. Baseline characteristics were similar, except for higher 24 h proteinuria in the CYC group. At 24 weeks, 37 patients in each group achieved the primary end point. The complete remission rate was 50% in CYC and 54% in MMF group. Gastrointestinal symptoms were significantly more frequent in patients receiving MMF (52 vs. 4%). However, other adverse events were similar. Thus, low-dose intravenous CYC is comparable in safety and efficacy to oral MMF in the induction treatment of less severe LN.

Metformin in peritoneal dialysis: a pilot experience.

OBJECTIVE: In a number of patients, the antidiabetic drug metformin has been associated with lactic acidosis. Despite the fact that diabetes mellitus is the most common cause of end-stage renal disease (ESRD) and that peritoneal dialysis (PD) is an expanding modality of treatment, little is known about optimal treatment strategies in the large group of PD patients with diabetes. In patients with ESRD, the use of metformin has been limited because of the perceived risk of lactic acidosis or severe hypoglycemia. However, metformin use is likely to be beneficial, and PD might itself be a safeguard against the alleged complications. METHODS: Our study involved 35 patients with insulin-dependent type 2 diabetes [median age: 54 years; interquartile range (IQR): 47-59 years] on automated PD (APD) therapy. Patients with additional risk factors for lactic acidosis were excluded. Metformin was introduced at a daily dose in the range 0.5 - 1.0 g. All patients were monitored for glycemic control by blood sugar levels and HbA1c. Plasma lactic acid levels were measured weekly for 4 weeks and then monthly to the end of the study. Plasma and effluent metformin and plasma lactate levels were measured simultaneously. RESULTS: In this cohort, the median duration of diabetes was 18 years (IQR: 14 - 21 years), median time on PD was 31 months (IQR: 27 - 36 months), and median HbA1c was 6.8% (IQR: 5.9% - 6.9%). At metformin introduction and at the end of the study, the median anion gap was 11 mmol/L (IQR: 9 - 16 mmol/L) and 12 mmol/L (IQR: 9 - 16 mmol/L; p > 0.05) respectively, median pH was 7.33 (IQR: 7.32 - 7.36) and 7.34 (IQR: 7.32 - 7.36, p > 0.05) respectively, and mean metformin concentration in plasma and peritoneal fluid was 2.57 ± 1.49 mg/L and 2.83 ± 1.7 mg/L respectively. In the group overall, mean lactate was 1.39 ± 0.61 mmol/L, and hyperlactemia (>2 mmol/L to 5 mmol/L) was found in 4 of 525 plasma samples (0.76%), but the patients presented no symptoms. None of the patients registered a plasma lactate level above 5 mmol/L. We observed no correlation between plasma metformin and plasma lactate (r = 0.27). CONCLUSIONS: Metformin may be used with caution in APD patients with insulin-dependent type 2 diabetes. Although our study demonstrated the feasibility of metformin use in APD, it was not large enough to demonstrate safety; a large-scale study is needed.

Mucormycosis of the transplanted kidney with renal papillary necrosis.

The occurrence of renal allograft mucormycosis is uncommon, but its association with renal papillary necrosis has not been reported. We describe such an association in a patient who survived on peritoneal dialysis after nephrectomy and antifungal therapy.

Papillary necrosis with invasive fungal infections: a case series of 29 patients.

BACKGROUND: Renal papillary necrosis (RPN) is associated with a number of comorbid conditions. However, it has been rarely reported in patients with fungal infections of the kidney. METHODS: We analyzed medical records of our hospital for the last two decades and identified 29 patients with fungal infections and RPN. RESULTS: Among the 29 patients, there were 24 men and 5 women. The median (range) age at presentation was 31.2 years (2 days-73 years). Three patients (10%) were kidney transplant recipients. The remaining had varied co-existing medical conditions that included diabetes mellitus in 16 (55%) and septicemia in 4 (14%). Clinical features at presentation were fever and oliguric kidney failure in 17 patients and loin pain accompanied by passage of fleshy material per urethra in 11 (38%). Diagnosis was made ante-mortem in 17 (59%) patients. Twenty patients (69%) had infection limited to the kidneys, while in the rest, it was disseminated. Kidney involvement was bilateral in 17 patients (59%). Urinalysis showed pyuria in 23 (79%) and microhematuria in 8 (28%) patients. Fungal infections included candidiasis (69%), aspergillosis (21%) and zygomycosis (10%). Of the 17 patients in whom the diagnoses was made ante-mortem, 12 survived and 5 died. Overall mortality was observed in 48% of cases. CONCLUSIONS: We herein report a series of patients with RPN associated with fungal infections of the kidney. Presentation varies from asymptomatic urinary tract infection to severe kidney failure with poor outcome. High index of suspicion is necessary to reduce the associated high mortality in these patients.